The trichothecene mycotoxins are a group of sesquiterpenoid fungal metabolites that include some of the most potent protein synthesis inhibitors known. Since trichothecenes are frequently found in cereal grains and are recalcitrant to inactivation during milling and processing, they enter human foods. Of these, vomitoxin (VT) is encountered most often in the U.S. food supply. Ingestion of VT by mice dramatically increases serum IgA and induces pathologic effects that are highly analogous to the common human glomerulonephritis, IgA nephropathy. We hypothesize that oral exposure to trichothecene mycotoxins alters cytokine-mediated regulation of IgA production. Our overall goals are to understand the cellular and molecular mechanisms by which trichothecenes modulate IgA production within the mucosal and systemic compartments and relate these to potential health hazards associated with ingestion of these naturally-occurring mycotoxins. Using the mouse model, three (3) specific objectives are proposed. The first objective will be to identify and localize cell populations in Peyer's patches and spleen that contribute to in vivo trichothecene-induced cytokine superinduction of subsequent elevation of IgA secretion. Second, we will elucidate molecular mechanisms by which trichothecenes superinduce cytokine production in clonal and primary cell culture models. Third, we will relate gender and hormone specific effects observed in vivo for VT=- induced IgA nephropathy to cellular and molecular mechanistic models.